bims-malgli 2026-08-09 papers

Nat Rev Neurol. 2026 Aug 05.

Sci Transl Med. 2026 Aug 05. 18(861): eaee5876

Vorasidenib improves response to subsequent chemoradiation in a genetically engineered mouse model of IDH-mutant glioma.

The mutant isocitrate dehydrogenase 1/2 inhibitor (mIDHi) vorasidenib was recently incorporated into clinical treatment guidelines for IDH-mutant gliomas, although its impact on chemoradiation is unclear. Specifically, it is unknown whether upfront mIDHi exposure alters subsequent chemoradiation efficacy. Addressing this critical question has been challenging because of limited clinical data and a paucity of mIDHi-responsive preclinical glioma models. We first established that a genetic mouse model of IDH-mutant astrocytoma developed by our group was responsive to vorasidenib monotherapy. We then used this mouse to address whether mIDHi alters the response to chemoradiation after progression on mIDHi. Mice that received upfront vorasidenib followed by chemoradiation at progression had improved survival compared with control mice receiving vehicle followed by chemoradiation. We then compiled real-world data and early outcomes from 29 patients who were among the first to receive mIDHi followed by radiation with or without chemotherapy. Our study directly addresses uncertainty surrounding therapy sequencing that has emerged after introduction of vorasidenib as a first-line treatment for IDH-mutant glioma. Our empirical preclinical data demonstrate that prior mIDHi treatment enhances chemoradiation sensitivity of IDH-mutant glioma.

DOI: https://doi.org/10.1126/scitranslmed.aee5876

Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag179

Chromosomal instability is associated with paradoxical cGAS upregulation and impaired STING signaling shaping the immune microenvironment in glioblastoma.

Hidenobu Yoshitake, Tetsuya Negoto, Mayuko Moritsubo, Takuya Furuta, Minji Jo, Toru Hirota, Kiyohiko Sakata, Hideo Nakamura, Motohiro Morioka.

Background: Glioblastoma (GBM) is characterized by pronounced chromosomal instability (CIN), which can activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and promote anti-tumor immunity. How CIN engages cGAS-STING in immunologically "cold" GBM and its relation to clinical outcomes remain unclear.
Methods: CIN was quantified in 74 tissue cores from 34 patients with isocitrate dehydrogenase-wildtype GBM by chromosome 7/10 fluorescence in situ hybridization; aneuploidy score (AS) and heterogeneity score were derived. Immunohistochemistry assessed cGAS, STING, phosphorylated IRF3 (p-IRF3), and immune markers (CD3, CD4, CD8, CD163, IBA-1). Polyploid giant cancer cells (PGCCs) were identified using hematoxylin and eosin staining. EGFR, PDGFRA, CDKN2A, and PTEN copy-number alterations were assessed by multiplex ligation-dependent probe amplification. The Cancer Genome Atlas (TCGA)-GBM cohort served as an independent dataset.
Results: High AS (≥1.36) was associated with longer overall survival (22.7 vs. 16.0 months, P = .039). cGAS expression correlated positively with AS (P = .019), consistent with cGAS engagement in highly aneuploid tumors. Conversely, STING was rarely expressed in tumor cells, restricted to stromal and vascular compartments, without accompanying immune infiltration. STING-positive regions were enriched for PGCCs (P = .045), suggesting stress adaptation rather than immune activation. p-IRF3 modestly correlated with AS (Spearman r = 0.39, P = .0006) and was reduced in EGFR-amplified or PTEN-loss cores (P = .003 each). In TCGA-GBM, surrogate AS stratification revealed a biphasic survival pattern consistent with our findings.
Conclusions: CIN was associated with cGAS upregulation but not functional STING-mediated immunity in GBM, suggesting that CIN-associated intrinsic stress adaptation may contribute to immunotherapy resistance in GBM.

Keywords: aneuploidy paradox; cGAS-STING; chromosomal instability; glioblastoma; polyploid giant cancer cells

DOI: https://doi.org/10.1093/noajnl/vdag179

Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag165

Intensive multimodal ketogenic metabolic therapy in glioblastoma: A clinical trial.

Matthew C L Phillips, Ziad Thotathil, Nur Azri Bin Haji Mohd Yasin, Charles de Groot, Alvin Tan, Marion Kuper-Hommel, Lee-Ann Creagh, Eric Ji, Nichola Naidoo, Mariska van Essen, Fouzia Ziad, Ben G Moon, Chris Frampton, Michael B Jameson.

Background: Glioblastoma (GBM), isocitrate dehydrogenase (IDH)-wildtype, has a median overall survival of 11-14 months despite standard treatment. Ketogenic metabolic interventions that lower the glucose ketone index (GKI) may improve outcomes. We evaluated the feasibility, tolerability, and potential clinical benefit of integrating standard treatment with an intensive multimodal metabolic therapy program (MTP) in newly diagnosed IDH-wildtype GBM.
Methods: Patients received standard chemoradiation and adjuvant chemotherapy alongside an MTP comprising prolonged fasting, time-restricted feeding, and a ketogenic diet. The primary outcome was the proportion sustaining a mean daily GKI ≤6 during chemoradiation. Secondary outcomes included GKI control throughout chemotherapy, body weight, body mass index, adverse events, performance, exercise, quality of life, and survival, compared with contemporary controls using unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results: Among 32 eligible patients, 18 commenced chemoradiation with the MTP (intention-to-treat), and 15 completed it (per-protocol). In the intention-to-treat population, 15 of 18 patients (83%) sustained a mean daily GKI ≤6 during chemoradiation. Among per-protocol patients, the GKI was 1.88 ± 0.56 during chemoradiation and 2.53 ± 0.86 throughout chemotherapy. Intentional weight loss averaged 17%, normalizing body mass index. MTP-related adverse events were mild or moderate. Exercise activity and quality of life improved. Median overall survival was 21.5 months versus 14.7 months in controls (HR = 0.42, 95% CI 0.18-0.97, P = .027), with 3-year survival of 27% versus 7%.
Conclusions: Intensive multimodal metabolic therapy was feasible, well-tolerated, and associated with improved exercise activity, quality of life, and survival outcomes, including higher 3-year survival.

Keywords: fasting; glioblastoma; glucose ketone index; ketogenic diet; metabolic therapy

DOI: https://doi.org/10.1093/noajnl/vdag165

Cell. 2026 Aug 03. pii: S0092-8674(26)00824-X. [Epub ahead of print]

Ultrarapid deep 3D histology enables intraoperative mapping of glioma infiltration.

Zhijie Liu, Yingying Li, Lingchao Chen, Minqian Wei, Mian Wei, Yuchen Sun, Tongqi Wang, Haixia Cheng, Xing Liu, Minbiao Ji, Lixue Shi.

Three-dimensional (3D) histology provides volumetric insights into tissue microarchitectures across entire specimens, holding great promise for more accurate prognostication. However, existing methods are too slow for intraoperative consultations. We present ULTRA (ultrarapid cleared stimulated Raman with AI), a label-free, stain-free, fixation-free, and section-free platform that leverages the chemical specificity of stimulated Raman scattering (SRS) microscopy for rapid 3D histological analysis. Through the synergistic development of a one-step tissue-clearing protocol and unsupervised learning algorithms, ULTRA delivers high-resolution, formalin-fixed, paraffin-embedded (FFPE)-grade deep 3D virtual histology within 30 min, covering orders of magnitude more tissue than slide-based methods. In human surgical glioma samples, ULTRA accurately resolves key histological features in 3D and delineates depth-dependent tumor infiltration margins at single-cell resolution. By compressing 3D histology from days or hours to an intraoperative timescale, ULTRA addresses a critical clinical gap and enables more informed surgical decision-making in the operating room.

Keywords: 3D histology; diffusion model; gliomas; intraoperative histology; label free; section free; stimulated Raman scattering; tissue clearing

DOI: https://doi.org/10.1016/j.cell.2026.07.026